Multiphase pharmaceutical formulations

ABSTRACT

The invention provides a multiphase pharmaceutical composition for combatting skin and anorectal conditions requiring medication comprising at least one phase containing one or more medicaments for combatting said disease and at least one porous phase containing a silicone oil absorbed therein and adapted for release, preferably delayed release, of the silicone oil whereby application of said composition at a region affected by said skin or anorectal condition deposits said medicament or medicaments thereon and a layer of silicone oil is formed thereover thus protecting the medicaments from erosion by aqueous media.

This invention concerns pharmaceutical formulation for the treatment ofskin and anorectal conditions.

Skin diseases commonly require the frequent application of medicaments.It is commonly preferably to leave the site of application uncoveredalthough there is then a tendency for the medicament to be removed bycontact with moisture. This is particularly true in the cases ofanorectal diseases such as haemorrhoids and anal fissures which arecommonly treated with combinations of astringents, antiseptics, topicalanalgesics, vasoconstrictors, antispasmodics and antiinflammatorysteroids. However, the healing of the lesions is commonly inhibited bythe mucous environment which, for example, leads to maceration of moistperianal skin.

One possible solution to this problem would be to apply medicaments inan occlusive layer which would repel water from the treated area.However, such conditions tend also to cause retention of fluids producedby the tissues, so that such an occlusive layer, by producing macerationof the affected area would thereby exacerbate the problem.

Furthermore, it is difficult to ensure that the occlusive layer does notform a barrier to prevent the medicaments from reaching the intendedsite of application.

On the other hand, at internal sites a deposited occlusive layer, forexample of suppository base containing medicaments, is subject toerosion by aqueous media which can quickly reduce the beneficial effectof the medicament(s).

Our copending International Patent Application No. PCT/GB89/01545describes and claims a multiphase pharmaceutical composition forcombatting an anorectal disease comprising at least one phase containingone or more medicaments for combatting said disease and at least onephase adapted for delayed release of a silicone oil whereby applicationof said composition at a region affected by said disease deposits saidmedicament or medicaments thereon and a layer of silicone oil is formedthereover, so protecting the medicaments from erosion by aqueous media.

In our above International application, the means for delayed release ofsilicone oil include microcapsules containing the silicone oil whichrelease the latter on rupture of the microcapsule shell, for example bypressure, dissolving or melting. The present invention is based on theconcept of using, as the means for delayed release of silicone oil, oneor more porous phases having silicone oil absorbed therein.

According to the present invention therefore we provide a multiphasepharmaceutical composition for combatting skin and anorectal conditionsrequiring medication comprising at least one phase containing one ormore medicaments for combatting said disease and at least one porousphase containing a silicone oil absorbed therein and adapted forrelease, preferably delayed release, of the silicone oil wherebyapplication of said composition at a region affected by said skin oranorectal condition deposits said medicament or medicaments thereon anda layer of silicone oil is formed thereover thus protecting themedicaments from erosion by aqueous media.

It will be appreciated that by being released after the application ofthe medicament, the silicone oil does not form a barrier between themedicament and the skin but forms a layer over the medicament whichprotects it from erosion while allowing the passage of water vapour andthus avoiding some of the problems of occlusive layers.

Skin conditions which may usefully be treated by compositions accordingto the invention include eczema, dermatitis, dry skin, chapped skin,napkin rash, pruritis and mild burns such as sunburn.

The porous phase(s) may be adapted to release the silicone oil bydiffusion, possibly aided by the action of pressure to compress theparticles, dissolution or melting.

In general, the porous phase(s) comprise porous particles.

A wide range of porous particles are available, as described inInternational Patent Applications WO088/01164 and W089/10132, U.S. Pat.Nos 4,873,091 and 4,690,825 and European Patent Application 306236A, thecontents of which are incorporated herein by reference.

In such porous particles, the total pore volume is preferably in therange 0.1 to 2.0 ml/g, more preferably 0.3 to 1.0 ml/g. The diameters ofthe particles will generally be in the range 1 to 1000 microns,preferably 5 to 100 microns, more preferably 10 to 50 microns: thesurface area of the particles will generally range from about 1 to 500m² /g, preferably 20 to 200 m² /g.

The porous particles may be composed of a wide range of materials. Manyorganic, synthetic polymers are suitable, as well as natural substancessuch as cellulose or gelatin. The choice of material will depend in parton the intended means of delayed release of the silicone oil, i.e.diffusion, compression, dissolving or melting.

Where diffusion of the silicone oil is intended, the porous particlesmay be relatively rigid. This has the advantage that the outermost poresdo not collapse when the oil diffuses out and thus do not block thediffusion of the oil from the inner pores. Such rigidity can becontrolled by the degree of cross-linking of polymeric materials ofwhich the particles are composed. The degree of cross-linking willgenerally be at least 10%, more usually in the range 20 to 80%, forexample 25 to 60%.

Polymers of which the particles may be formed include polyolefins,including polyethylene, polystyrene, polydicyclopentadiene etc.;polyacrylate esters, e.g. optionally alkoxylated C₁₋₁₀ alkyl,cycloalkyl, aryl or aralkyl esters of polyacrylic or polymethacrylicacids; polyvinyl esters e.g. polyvinyl acetate or polyvinyl laurate;polyvinyl ketones, e.g. polyvinylmethyl ketone; and polyvinyl ethers,e.g. polyvinylpropyl ether.

The silicone oil will preferably be a polydialkylsiloxane oil, morepreferably polydimethylsiloxane. Suitable medical grade silicone oilsinclude Dow Corning 360 Medical Fluid.

In one embodiment of the invention the composition comprises a creamcontaining the medicament(s) together with porous particles containingsilicone oil which release said oil after application of the compositionto the affected area.

As indicated above, the porous particles in such a cream may liberatethe silicone oil by diffusion, pressure, dissolving or melting. It ispreferred that the particles are elastically compressable so that afterfirst application of the cream whereby the medicament contacts theinfected area, application of gentle pressure, for example by rubbing,causes rapid release of the silicone oil to provide a coating of oilover the layer of cream.

Elastically compressable particles may be composed of elastomers, suchas those described in U.S. Pat. No. 4,873,091, including for example,isoprene rubbers, butadiene rubbers, chloroprene rubbers, styrenebutadiene. Particularly useful are ethylene-propylene-diene terpolymers,wherein the diene components may be straight chain diolefins, cyclicdienes and bicyclic dienes. Examples of such dienes include1,4-hexadiene, dicyclopentadiene and ethylidene norbornene. Siliconerubbers may also be used.

Porous particles which dissolve, primarily in aqueous body fluids, maybe composed of water-soluble gels including gelatin, agarose etc andcertain polymethyl methacrylates such as Eudragit (Rohm, Darmstadt)which dissolve at the pH of the rectum.

Porous particles which melt may be composed of fats and waxes of thetype used in suppositories which melt at body temperatures but which aresolid at room temperature as well as gelatin.

The phase in which the medicament(s) are contained may be a conventionalcream base, e.g. containing oily or waxy materials such as liquidparaffin, white petroleum or cetyl alcohol, water and one or moresurfactants to produce a water-in-oil emulsion. A bactericide such asbenzalkonium chloride is conveniently present.

Medicaments which may usefully be present include astringents such asbismuth subgallate, local anaesthetics such as benzocaine or lignocane,cortico steroid, antiinflammatory steroids such as hydrocortisoneacetate, antibacterials and emollients.

According to a further embodiment of the invention, compositions for thetreatment of anorectal diseases take the form of a suppositorycomprising an outer layer containing the medicament in a suppositorybase surrounding one or more porous phases containing the silicone oil.

The suppositories may be provided with a gauze attachment as describedin our International Patent Application No. PCT/GB89/01547 to assistlocation in the anorectal area.

The medicaments and silicone oil may be as described above for thecreams according to the invention.

The suppository base may, for example, be any conventional suppositorybase material such as glycogelatin, polyethylene glycol, fractionatedpalm kernel oil or, more preferably, one or more natural, synthetic orsemisynthetic hard fats such as cocoa butter. A particularly preferredmaterial is one of the range of cocoa butter products sold under thetrade name Witepsol by Dynamit Nobel, Slough, England.

The porous phase(s) may conveniently be porous particles which may bedispersed throughout the suppository base or, more preferably, areconcentrated in the interior of the suppository.

The porous phase may also be a single, relatively large porous body. Ifthis is readily compressible, i.e. of a spongy consistency, it willrelease a substantial volume of the silicone oil by pressure from thewalls of the rectum. If this porous body is located in the centre of thesuppository, release of the silicone oil will be delayed until thesuppository base has melted, thus allowing the medicament to contact theaffected area before being coated by the silicone oil.

However, the porous body containing the silicone oil may comprise oneside of an asymmetrical suppository in which the other side is thesupository base carrying the medicament. Such an asymmetricalsuppository may be of use where the affected area is localised on oneside of the anus and can then be inserted in such a way that thesuppository base with medicament contacts the affected are a while thesilicone oil-containing porous body overlies this and releases siliconeoil by pressure of the walls of the anus. In this case, the silicone oilmay begin to be released immediately on application, i.e. release willnot be delayed until after melting of the suppository base. However, theporous body with absorbent silicone oil will overlie and thus protectsuppository base in the immediate vicinity of application while siliconeoil will exude to cover more widespread melted suppository base.

Suppositories according to the invention can be made in any convenientway,. Thus, for example, the outer suppository layer may be cast inconventional suppository moulds into which one or more pins or rodsprotrude longitudinally. After solidification, the pins may be removed,the moulds may be inverted and the phase containing the silicone oilintroduced into the cavity left by removal of the pins. If the materialso introduced does not fill the cavities completely, the remainder ofthe space can advantageously be filled with further suppository basematerial to ensure that the silicone oil-containing phase is completelysurrounded by suppository base material. Where the porous phasecomprises porous particles, these may be simply distributed throughoutthe melted suppository base and the suppositories may then be castconventionally.

Porous materials for use in compositions of the invention may be made inany convenient way. Thus, it is possible to polymerise one or moresuitable monomers in the presence of a dispersed porogen: afterpolymerisation, the porogen may be removed, e.g. by evaporation orsolvent extraction, to provide a network of interconnected pores. Thesilicone oil can then be absorbed into the porous material, if desiredby first evacuating air from the pores. The silicone oil can, however,itself be used as the porogen: the silicone oil may be dispersed indroplets throughout a monomer with which it is immiscible so that afterpolymerisation the silicone effectively fills pores within the polymericmaterial. In general, however, it is preferred to prepare the porousmaterial first in order to remove rigorously all traces of monomer,catalysts and cross-linking agents, before introduction of silicone oil.

A number of possible methods of manufacture of porous material, inparticular porous particles, are described in the prior patents listedabove.

In general, porous particles may conveniently be produced by emulsion orsuspension polymerisation in a liquid - liquid system. Thus, forexample, a solution comprising the chosen water-immisicible monomer, anycross-linking agent required, a catalyst, if needed, and a porogen whichis misicible with the solution but immisicible with water. The solutionis then suspended in an aqueous solution, which may contain one or moresuspending agents or surfactants and polymerisation is initiated e.g. byraising the temperature or by irradiation. The porogen is then removedfrom the solidified particles, e.g. by evaporation or extraction into asolvent which is substantially inert to the polymer.

Examples of such porogens include C₅₋₁₂ alkanes, C₅₋₈ cycloalkanes andaromatic solvents such as benzene toluene etc. The particles willnormally be washed thoroughly to remove contaminants, using solventssuch that the final solvent can be removed by evaporation.

In general, particle diameter may be controlled by the degree ofagitation to prepare the initial emulsion. The pore diameter and porevolume are controlled by the amount of porogen used and the degree ofcross-linking.

The monomers used to prepare the particles may be any of thoseappropriate to make the polymers set out above. Suitable cross-linkingagents for mono-olefins include poly-ethylenically unsaturated monomers.

The following Examples are given by way of illlustration only:

EXAMPLE 1

    ______________________________________                                        Cream                                                                                                %                                                      ______________________________________                                        Dow Corning 360 Silicone oil (dimethasone)                                                             10                                                   absorbed in polystyrene-divinylbenzene                                        porous beads, mean particle diameter                                          30 microns, pore volume 0.5 ml/g                                              Liquid paraffin          22.75                                                White petrolatum         8.0                                                  Cetyl alcohol            7.0                                                  Span 60                  3.0                                                  Benzocaine               2.5                                                  Bismuth subgallate       2.0                                                  Potassium dihydrogen phosphate                                                                         0.5                                                  1% Aqueous Benzalkonium chloride                                                                       10.0                                                 Tween 60                 5.0                                                  70% Aqueous sorbitol     5.0                                                  Hydrocortisone acetate   0.5                                                  Water                    23.75                                                ______________________________________                                    

The oily phase comprising the liquid paraffin, white petrolatum, cetylalcohol and Span 60 are mixed at 60°. The aqueous phase comprising theremaining components except the porous beads is also blended at 60° C.and the two phases combined and blended. The porous beads are addedsubsequently and dispersed throughout the cream.

EXAMPLE 2

    ______________________________________                                        Suppository                                                                   ______________________________________                                        Dow Corning 360 Silicone oil (dimethasone)                                                             10%                                                  absorbed in polystyrene-divinylbenzene                                        porous beads, mean particle diameter                                          30 microns, pore volume 0.5 ml/g                                              Bismuth subgallate       2.0 g                                                Benzocaine               2.5 g                                                50% Benzalkonium chloride                                                                              0.2 g                                                Hydrocortisone acetate   0.5 g                                                Witepsol S55 suppository base                                                                          72.15 g                                              Witepsol E85 suppository base                                                                          12.65 g                                              ______________________________________                                    

The above components apart from the porous particles containing siliconeoil are blended at 55° C., cooled to 40° C. and poured into 50 moulds asshown in FIG. 1 hereinafter. After cooling, the pins are withdrawn, themoulds are inverted and porous particles introduced into the cavity leftby each pin. The remainder of the cavity is filled with a blend of thetwo Witepsol bases at 40° C. After chilling, the suppositories areremoved from the moulds and packaged.

We claim:
 1. A multiphase pharmaceutical composition for combatting skinand anorectal conditions requiring medication comprising at least onephase containing a therapeutically effective amount of one or moremedicaments for combatting said disease and at least one porous phasecontaining a silicone oil absorbed therein and adapted for release ofthe silicone oil whereby application of said composition at a regionaffected by said skin or anorectal condition deposits said medicament ormedicaments thereon and a layer of silicone oil is formed thereover thusprotecting the medicaments from erosion by aqueous media.
 2. Acomposition as claimed in claim 1, wherein said porous phase is adaptedfor delayed release of the silicone oil.
 3. A composition as claimed ineither of claims 1 or 2, comprising a cream containing the medicament(s)together with porous particles containing silicone oil which releasesaid oil after application of the composition to the affected area.
 4. Acomposition as claimed in claim 3, wherein said particles areelastically compressible.
 5. A composition as claimed in claim 1 or 2 inthe form of a suppository comprising an outer layer containing themedicament in a suppository base surrounding one or more porous phasescontaining the silicone oil.
 6. A composition as claimed in claim 5,wherein said porous phase comprises porous particles which areconcentrated in the interior of said suppository.
 7. A composition asclaimed in claim 1 or 2 in the form of a suppository, wherein the porousphase and the medicaments are positioned asymmetrically.
 8. Acomposition as claimed in claim 3 in the form of a suppositorycomprising an outer layer containing the medicament in a suppositorybase surrounding one or more porous phases containing the silicone oil.9. A composition as claimed in claim 4 in the form of a suppositorycomprising an outer layer containing the medicament in a suppositorybase surrounding one or more porous phases containing the silicone oil.10. A composition as claimed in claim 8 wherein said porous phasecomprises porous particles which are concentrated in the interior ofsaid suppository.
 11. A composition as claimed in claim 9 wherein saidporous phase comprises porous particles which are concentrated in theinterior of said suppository.
 12. A composition as claimed in claim 3 inthe form of a suppository, wherein the porous phase and the medicamentsare positioned asymmetrically.
 13. A composition as claimed in claim 4in the form of a suppository, wherein the porous phase and themedicaments are positioned asymmetrically.